Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers

Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14379-84. doi: 10.1073/pnas.2336093100. Epub 2003 Nov 6.


The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to delta-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA C alpha translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-beta gamma dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by beta gamma dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / metabolism*
  • Animals
  • Arachidonic Acids / pharmacology
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dimerization
  • Dopamine Agonists / pharmacology
  • Drug Synergism
  • Enkephalin, Leucine-2-Alanine / pharmacology
  • Ethanol / pharmacology
  • GTP-Binding Protein beta Subunits / chemistry
  • GTP-Binding Protein beta Subunits / metabolism*
  • Isoenzymes / metabolism
  • Models, Neurological
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Adenosine A2 / metabolism
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism
  • Substance-Related Disorders / metabolism*


  • Arachidonic Acids
  • Dopamine Agonists
  • GTP-Binding Protein beta Subunits
  • Isoenzymes
  • Receptor, Cannabinoid, CB1
  • Receptors, Adenosine A2
  • Receptors, Opioid, delta
  • methanandamide
  • Ethanol
  • Enkephalin, Leucine-2-Alanine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • Cyclic AMP-Dependent Protein Kinases
  • protein kinase A Calpha
  • Adenosine